In the beginning of 20th century, the Nobel Prize-winning German scientist Paul Ehrlich proposed the idea of “magic bullet” for future drug development, i.e., an ideal drug that would selectively destroy diseased cells without affecting healthy cells. In the past several decades, scientists have been exploring to develop such ideal drugs.
In the 1970s, targeted drug delivery system was developed and widely used for the treatment of cancer. It was reported that targeted anti-cancer drugs accounted for more than 30% of the world's anti-cancer drug sales, and that this figure is forecasted to rise to 55% in 2025. Meanwhile, with the advancement in research, new targeted drug delivery carriers has emerged, the routes of administration has been broadened, and targeted drug delivery system has been expanded to treat many diseases other than cancer.
Developing targeted drugs for respiratory diseases is one of the hotspots of the research, which is primarily focused on the following areas:
1. Targeted treatment of airways diseases by inhalation. Starting from the earlier 1950s, inhaled corticosteroids have been used for the treatment of asthma and COPD. Since then, with improvement in inhaled drugs and devices, inhaled corticosteroids have become the main therapeutic agents for the treatment of asthma and COPD. However, inhaled drugs are mainly suitable for topical treatment of airways diseases, and are not effective against parenchyma and interstitial lung diseases due to low bioavailability.
2. Passive lung-targeting drugs through drug carriers. Currently, a variety of drug carriers such as liposomes, microparticles, microspheres have been researched for lung-targeted drug delivery. However, these passive targeting drugs have poor tissue selectivity, and cannot avoid significant residue in the liver, spleen and other organs. Therefore, they don't achieve optimal targeting effect.
The ligand-receptor or antigen-antibody binding is a special recognition mechanism of the human body, and as reported in the literature, this mechanism can achieve active drug targeting to enhance drug efficacy and reduce the side effects. For example, a composite drug made of paclitaxel liposome and a monoclonal antibody against the epidermal growth factor has anti-tumor effect that is 25 times greater that of the drug without the monoclonal antibody. Thus, to achieve ideal active lung targeting effect, it is critical to find a receptor in the lung tissue with high specificity and prepare a targeting ligand with high affinity. Studies have shown that pulmonary alveolar type II epithelial cells in the lung tissue have proliferation and secretion functions, and account for 16% of the total cells in lung parenchyma. Type II cells can synthesize and secrete pulmonary surfactant. The main components of the pulmonary surfactant are lipids (90%) and proteins (10%), and the proteins are specific pulmonary surfactant proteins (SP). SP has been named as SP-A, SP-B, SP-C, SP-D, SP-A based on the order it was discovered, and SP-A was discovered first, and has strong expression in pulmonary alveolar type II epithelial cells with abundant signals, and is rarely expressed in other tissues. Thus, SP-A is highly lung-specific, and is an ideal receptor in the lung tissue with specificity.
In addition to high affinity, an ideal targeting ligand should also have a small molecular weight, high tissue penetration, and weak immunogenicity. Antigen-antibody binding is the strongest recognition mechanism, and therefore antibody is the preferred ligand. However, although of high affinity, full antibodies have large molecular weight (with a relative molecular weight of 150,000), weak tissue penetration and strong immunogenicity, and are not ideal ligands. With the development of antibody and gene engineering technologies, antibody fragments (Fab, ScFv) now have the advantages of small molecular weight and weak immunogenicity, but they has lower stability and affinity than full antibodies.
In 1993, scientists from Belgian first reported the existence of Heavy Chain antibody (HCAbs) without the light chain in the blood of camelids. The variable domain (VHH) of the heavy chains of HCAbs has a complete and independent antigen-binding capacity, and if cloned, a single domain antibodies in the nanometer scale can be obtained, which are known as Nanobodies® (Nbs). Nanobody has many advantages as a ligand: 1) small molecular weight, strong tissue penetration, and high affinity. It has the least molecular weight among the known antibody molecules, with a molecular weight of only 15,000; its ability to penetrate tissues is significantly superior to full antibody, and its affinity with specific antigen is of nmol scale. 2) Stable structure. It can maintain high degree of stability even if stored at 37° C. for a week, under high temperature (90° C.), or under strong denaturing conditions such as being exposed to chaotropic agent, protease and strong PH value. 3) Weak immunogenicity. AS its gene has high homology with human VH III family, it has weak immunogenicity and good biocompatibility. Because of these advantages, nanobody has been studied extensively as a new antibody drug, but its use as targeted ligand for SP-A has not been reported.